DNA damage-induced MDMX degradation is mediated by MDM2
Open accessAbstract
Although genetic studies have demonstrated that MDMX is essential to maintain p53 activity at low levels in non-stressed cells, it is unknown whether MDMX regulates p53 activation by DNA damage. We show here that DNA damage-induced p53 induction is associated with rapid down-regulation of the MDMX protein. Significantly, interference with MDMX down-regulation results in the suppression of p53 activation by genotoxic stress. We also demonstrate that DNA damage-induced MDMX reduction is mediated by MDM2, which targets MDMX for proteasomal degradation by a distinct mechanism that permits preferential MDMX degradation and therefore ensures optimal p53 activation.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Mdm2 undergoes auto-degradation and targets Mdmx for degradation, which is critical for optimal p53 activation after stress.
“However, in addition to degrading p53, Mdm2 also undergoes auto-degradation [12,13] and targets Mdmx for degradation [14–16], which is critical for optimal p53 activation after stress.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [15]
MDMX can be ubiquitinated and degraded by MDM2.
“Several reports showed that MDMX can be ubiquitinated and degraded by MDM2 (De Graaf et al, 2003;Kawai et al, 2003;Pan and Chen, 2003).”
From ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage (2005) · cites this paper as Kawai et al, 2003
DNA damage induces MDMX degradation in p53-deficient cells without induction of MDM2.
“A recent study showed that DNA damage also induces MDMX degradation in p53-deficient cells, without induction of MDM2 (Kawai et al, 2003).”
From ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage (2005) · cites this paper as Kawai et al, 2003
Cites
p53, the cellular gatekeeper for growth and division
Levine, A. J. (1997) · Cell · doi:10.1016/s0092-8674(00)81871-1 · Cited by 7,693 · see citing works
A DNA vector-based RNAi technology to suppress gene expression in mammalian cells
Sui, G., Soohoo, C., Affar, E. B., Gay, F., Shi, Y. G., Forrester, W. C., & Shi, Y. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.082117599 · Cited by 1,103 · see citing works
Mdm2 Is a RING Finger-dependent Ubiquitin Protein Ligase for Itself and p53
Fang, S., Jensen, J. P., Ludwig, R. L., Vousden, K. H., & Weissman, A. M. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.12.8945 · Cited by 1,044 · see citing works
MDMX: a novel p53‐binding protein with some functional properties of MDM2.
Shvarts, A., Steegenga, W. T., Riteco, N., van Laar, T., Dekker, P., Bazuine, M., van Ham, R. C., van der Houven van Oordt, W., Hateboer, G., van der Eb, A. J., et al. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00919.x · Cited by 648 · see citing works
Parant, J., Chavez-Reyes, A., Little, N. A., Yan, W., Reinke, V., Jochemsen, A. G., & Lozano, G. (2001) · Nature Genetics · doi:10.1038/ng714 · Cited by 517 · see citing works
Regulation of p53 function and stability by phosphorylation.
Ashcroft, M., Kubbutat, M. H. G., & Vousden, K. H. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.3.1751 · Cited by 452 · see citing works
Honda, R., & Yasuda, H. (2000) · Oncogene · doi:10.1038/sj.onc.1203464 · Cited by 376 · see citing works
Activation of the p53 tumor suppressor protein
Vousden, K. H. (2002) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/s0304-419x(02)00035-5 · Cited by 337 · see citing works
Migliorini, D., Denchi, E. L., Danovi, D., Jochemsen, A., Capillo, M., Gobbi, A., Helin, K., Pelicci, P. G., & Marine, J.-C. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.15.5527-5538.2002 · Cited by 313 · see citing works
Stabilization of the MDM2 Oncoprotein by Interaction with the Structurally Related MDMX Protein
Sharp, D. A., Kratowicz, S. A., Sank, M. J., & George, D. L. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.53.38189 · Cited by 286 · see citing works
Mutual Dependence of MDM2 and MDMX in Their Functional Inactivation of p53
Gu, J., Kawai, H., Nie, L., Kitao, H., Wiederschain, D., Jochemsen, A. G., Parant, J. M., Lozano, G., & Yuan, Z.-M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c200150200 · Cited by 265 · see citing works
Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms
Stad, R., Little, N. A., Xirodimas, D. P., Frenk, R., van der Eb, A. J., Lane, D. P., Saville, M. K., & Jochemsen, A. G. (2001) · The EMBO Reports · doi:10.1093/embo-reports/kve227 · Cited by 234 · see citing works
mdmx is a negative regulator of p53 activity in vivo.
Finch, R. A., Donoviel, D. B., Potter, D., Shi, M., Fan, A., Freed, D. D., Wang, C.-Y., Zambrowicz, B., Ramírez‐Solis, R., Sands, A., et al. (2002) · PubMed · Cited by 192 · see citing works
Critical Contribution of the MDM2 Acidic Domain to p53 Ubiquitination
Kawai, H., Wiederschain, D., & Yuan, Z.-M. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.14.4939-4947.2003 · Cited by 122 · see citing works
Kawai, H., Nie, L., & Yuan, Z.-M. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.17.6079-6088.2002 · Cited by 57 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Regulating the p53 pathway: in vitro hypotheses, in vivo veritas
Toledo, F., & Wahl, G. M. (2006) · Nature reviews. Cancer · doi:10.1038/nrc2012 · Cited by 1,286 · see citing works
“A crucial step in DNA-damage-mediated p53 activation involves both MDM2 auto-degradation and MDM2-dependent degradation of MDM4 (Ref”
BackgroundAwakening guardian angels: drugging the p53 pathway
Brown, C. J., Lain, S., Verma, C. S., Fersht, A. R., & Lane, D. P. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2763 · Cited by 881 · see citing works
“Another consequence of MDM2–MDM4 heterodimerization is that MDM4 can be ubiquitylated by MDM2and is consequently degrade”
BackgroundCoping with stress: multiple ways to activate p53
Horn, H. F., & Vousden, K. H. (2007) · Oncogene · doi:10.1038/sj.onc.1210263 · Cited by 522 · see citing works
“…(Sharp et al., 1999; Tanimura et al., 1999), which results in the stabilization of Mdm2 (Stad et al., 2001; Gu et al., 2002) or the Mdm2-mediated degradation of MdmX (de Graaf et al., 2003; Kawai et al., 2003; Pan and Chen, 2003), depending on the relative expression levels of the two proteins.”
BackgroundInfluentialThe p53 orchestra: Mdm2 and Mdmx set the tone
Wade, M., Wang, Y. V., & Wahl, G. M. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.01.009 · Cited by 450 · see citing works
“However, in addition to degrading p53, Mdm2 also undergoes autodegradation [12,13] and targets Mdmx for degradation [14–16], which is critical for optimal Wade et al.”
BackgroundStructural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX
Pazgier, M., Liu, M., Zou, G., Yuan, W., Li, C., Li, C., Li, J., Monbo, J., Zella, D., Tarasov, S. G., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900947106 · Cited by 391 · see citing works
Targeting the MDM2-p53 Interaction for Cancer Therapy
Shangary, S. K., & Wang, S. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-5136 · Cited by 364 · see citing works
The Roles of MDM2 and MDMX in Cancer
Karni-Schmidt, O., Lokshin, M., & Prives, C. L. (2016) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-012414-040349 · Cited by 294 · see citing works
Meulmeester, E., Maurice, M. M., Boutell, C., Teunisse, A. F. A. S., Ovaa, H., Abraham, T. E., Dirks, R. W., & Jochemsen, A. G. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.04.024 · Cited by 260 · see citing works
“Lastly, treatment of cells with DNA damaging agents results in an Hdm2-dependent degradation of Hdmx (Pan and Chen, 2003; Kawai et al., 2003a). Remarkably, we find that ectopically expressed HAUSP is unable to rescue DNA damagemediated degradation of Hdmx. It could be hypothesized that not the decrease in HAUSP activi…”
BackgroundMDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation
Wang, C., Ivanov, A. V., Chen, L., Fredericks, W. J., Seto, E., Rauscher, F. J., & Chen, J. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600791 · Cited by 263 · see citing works
“MDM2 is an ubiquitin E3 ligase that promotes ubiquitination of itself, p53, and several other cellular proteins, including androgen receptor, Tip60, glucocorticoid receptor, and the MDM2 homolog MDMX (De Graaf et al, 2003; Kawai et al, 2003a; Pan and Chen, 2003).”
BackgroundATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage
Chen, L., Gilkes, D. M., Pan, Y., Lane, W. S., & Chen, J. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600812 · Cited by 260 · see citing works
“A recent study showed that DNA damage also induces MDMX degradation in p53-deficient cells, without induction of MDM2 (Kawai et al, 2003).”
BackgroundResultInfluentialMechanism of p53 stabilization by ATM after DNA damage
Cheng, Q., & Chen, J. (2010) · Cell Cycle · doi:10.4161/cc.9.3.10556 · Cited by 248 · see citing works
MDMX overexpression prevents p53 activation by the MDM2 inhibitor Nutlin
Hu, B., Gilkes, D. M., Farooqi, B., Sebti, S. M., & Chen, J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.c600147200 · Cited by 236 · see citing works
Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization
Graves, B., Thompson, T., Xia, M., Janson, C., Lukacs, C., Deo, D., Di Lello, P., Fry, D., Garvie, C., Huang, K.-S., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1203789109 · Cited by 230 · see citing works
“On the other hand, MDM2 can also ubiquitinate MDMX and is, therefore, responsible for its stability as well (11, 12).”
BackgroundMarine, J.-C. W., Dyer, M. A., & Jochemsen, A. G. (2007) · Journal of Cell Science · doi:10.1242/jcs.03362 · Cited by 228 · see citing works
“Several groups have shown that Mdm2 can bind to and ubiquitylate Mdmx to stimulate its proteasome-dependent degradation (Pan and Chen, 2003; de Graaf et al., 2003; Kawai et al., 2003).”
BackgroundEfficient p53 Activation and Apoptosis by Simultaneous Disruption of Binding to MDM2 and MDMX
Hu, B., Gilkes, D. M., & Chen, J. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1140 · Cited by 214 · see citing works
Ribosomal Protein S7 Is Both a Regulator and a Substrate of MDM2
Zhu, Y. Y., Poyurovsky, M. V., Li, Y., Biderman, L., Stahl, J., Jacq, X., & Prives, C. L. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.07.014 · Cited by 206 · see citing works
“, 2001) Normally cytoplasmic, upon DNA damage, MDMX is recruited to the nucleus where it is degraded by MDM2, presumably to augment the function and stability of p53 under such conditions (Kawai et al., 2003; LeBron et al., 2006; Pereg et al., 2005).”
InfluentialToledo, F., Krummel, K. A., Lee, C. J., Liu, C.-W., Rodewald, L.-W., Tang, M., & Wahl, G. M. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.03.014 · Cited by 199 · see citing works
“However, several recent reports reveal another role for Mdm2 in p53 control: Mdm2 auto-degradation and Mdm2-dependent degradation of Mdm4 after DNA damage (Chen et al., 2005; Kawai et al., 2003; Meulmeester et al., 2005; Okamoto et al., 2005; Pereg et al., 2005; Stommel and Wahl, 2004).”
BackgroundMdmx as an essential regulator of p53 activity
Marine, J., & Jochemsen, A. G. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.03.151 · Cited by 186 · see citing works
Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage
Pereg, Y., Shkedy, D., de Graaf, P., Meulmeester, E., Edelson-Averbukh, M., Salek, M., Biton, S., Teunisse, A. F. A. S., Lehmann, W. D., Jochemsen, A. G., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0408595102 · Cited by 181 · see citing works
Ribosomal Proteins RPL37, RPS15 and RPS20 Regulate the Mdm2-p53-MdmX Network
Daftuar, L., Zhu, Y. Y., Jacq, X., & Prives, C. L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0068667 · Cited by 173 · see citing works
“Upon some forms of cellular stress, MdmX is degraded, thus releasing p53 from inhibition [7,8], and Mdm2 and p53 are modified so that Mdm2 cannot bind to p53 and target it for degradation.”
BackgroundAn essential function of the extreme C-terminus of MDM2 can be provided by MDMX
Uldrijan, S., Pannekoek, W., & Vousden, K. H. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601469 · Cited by 170 · see citing works
“For example, the acidic domain in MDM2 has been shown to be important for the ubiquitylation and degradation of p53, although this region is not required for the E3 activity of the RING domain (Kawai et al, 2003b; Meulmeester et al, 2003).”
BackgroundTargeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry?
Wade, M., & Wahl, G. M. (2009) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-08-0423 · Cited by 170 · see citing works
“Phosphorylation of Mdm2 and Mdmx after DNA damage induces HAUSP dissociation, which increases Mdm2 autoubiquitination and transubiquitination of Mdmx and accelerates the turnover of both (28-31).”
BackgroundATM-Mediated Phosphorylations Inhibit Mdmx/Mdm2 Stabilization by HAUSP in Favor of p53 Activation
Meulmeester, E., Pereg, Y., Shiloh, Y., & Jochemsen, A. G. (2005) · Cell Cycle · doi:10.4161/cc.4.9.1981 · Cited by 166 · see citing works
Hdmx modulates the outcome of p53 activation in human tumor cells
Wade, M., Wong, E. T., Tang, M., Stommel, J. M., & Wahl, G. M. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m605405200 · Cited by 163 · see citing works
Regulation of p53 by the Ubiquitin-conjugating Enzymes UbcH5B/C in Vivo
Saville, M. K., Sparks, A., Xirodimas, D. P., Wardrop, J., Stevenson, L. F., Bourdon, J.-C., Woods, Y. L., & Lane, D. P. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m403362200 · Cited by 158 · see citing works
RING Domain–Mediated Interaction Is a Requirement for MDM2's E3 Ligase Activity
Kawai, H., Lopez-Pajares, V., Kim, M. M., Wiederschain, D., & Yuan, Z.-M. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1313 · Cited by 156 · see citing works
“It has been shown that DNA damage mediates MDM2-dependent degradation of MDMX, allowing for maximal p53 activation (11, 12).”
BackgroundActivation of the tumor suppressor p53 upon impairment of ribosome biogenesis
Bursać, S., Brdovčak, M. C., Donati, G., & Volarević, S. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.08.014 · Cited by 154 · see citing works
MDMX regulation of p53 response to ribosomal stress
Gilkes, D. M., Chen, L., & Chen, J. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601424 · Cited by 142 · see citing works
Regulation of p53: a collaboration between Mdm2 and MdmX
Pei, D., Zhang, Y., & Zheng, J. (2012) · Oncotarget · doi:10.18632/oncotarget.443 · Cited by 140 · see citing works
“com/oncotarget that DNA damage can destabilize Mdm2 by means of autoubiquitination [39,42] and Mdm2 ubiquitinates MdmX to mark it for proteasomal degradation [43,44].”
BackgroundPant, V., Xiong, S., Iwakuma, T., Quintás-Cardama, A., & Lozano, G. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1102241108 · Cited by 134 · see citing works
“Notably, Mdm4 was undetectable owing to its degradation after IR (21, 22).”
BackgroundOkamoto, K., Kashima, K., Pereg, Y., Ishida, M., Yamazaki, S., Nota, A., Teunisse, A., Migliorini, D., Kitabayashi, I., Marine, J.-C., et al. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.21.9608-9620.2005 · Cited by 129 · see citing works
“Activated p53 stimulates Mdmx cleavage by caspase-3 (11), and Mdm2 targets Mdmx for ubiquitination and degradation (8, 16, 32).”
BackgroundInfluentialMDM2 and MDMX: Alone and together in regulation of p53.
Shadfan, M., Lopez-Pajares, V., & Yuan, Z.-M. (2012) · PubMed · Cited by 125 · see citing works
Regulation of MDMX nuclear import and degradation by Chk2 and 14-3-3
LeBron, C., Chen, L., Gilkes, D. M., & Chen, J. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601032 · Cited by 122 · see citing works
“Several reports showed that MDMX can be ubiquitinated and degraded by MDM2 (de Graaf et al, 2003; Kawai et al, 2003; Pan and Chen, 2003).”
BackgroundUSP7 Is a Master Regulator of Genome Stability
Valles, G. J., Bezsonova, I., Woodgate, R., & Ashton, N. W. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00717 · Cited by 114 · see citing works
Quantitative analyses reveal the importance of regulated Hdmx degradation for p53 activation
Wang, Y. V., Wade, M., Wong, E., Li, Y.-C., Rodewald, L. W., & Wahl, G. M. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701497104 · Cited by 116 · see citing works
Mdm2 and MdmX partner to regulate p53
Wang, X., & Jiang, X. (2012) · FEBS Letters · doi:10.1016/j.febslet.2012.02.049 · Cited by 111 · see citing works
“p53/Mdm2 feedback loop through self-destruction [56,57].”
USP7 - a crucial regulator of cancer hallmarks
Saha, G., Roy, S., Basu, M., & Ghosh, M. K. (2023) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2023.188903 · Cited by 106 · see citing works
Discovery of Mdm2-MdmX E3 Ligase Inhibitors Using a Cell-Based Ubiquitination Assay
Herman, A. G., Hayano, M., Poyurovsky, M. V., Shimada, K., Skouta, R., Prives, C., & Stockwell, B. R. (2011) · Cancer Discovery · doi:10.1158/2159-8290.cd-11-0104 · Cited by 100 · see citing works
“Mdm2 can also directly ubiquitinate and degrade MdmX upon DNA-damage stimuli (20-22).”
MdmX is a substrate for the deubiquitinating enzyme USP2a
Allende-Vega, N., Sparks, A., Lane, D. P., & Saville, M. K. (2010) · Oncogene · doi:10.1038/onc.2009.330 · Cited by 100 · see citing works
p53 is activated in response to disruption of the pre-mRNA splicing machinery
Allende-Vega, N., Dayal, S., Agarwala, U., Sparks, A., Bourdon, J., & Saville, M. K. (2012) · Oncogene · doi:10.1038/onc.2012.38 · Cited by 96 · see citing works
Differential Roles of ATM- and Chk2-Mediated Phosphorylations of Hdmx in Response to DNA Damage
Pereg, Y., Lam, S., Teunisse, A., Biton, S., Meulmeester, E., Mittelman, L., Buscemi, G., Okamoto, K., Taya, Y., Shiloh, Y., et al. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00562-06 · Cited by 93 · see citing works
“The importance of Hdmx as a negative regulator of p53 gains support from the observation that degradation of Hdmx after DNA damage is essential for a proper p53 response, as evidenced by p53 stabilization, p21 induction, and activation of cell cycle checkpoints (21).”
BackgroundModulation of p53 and MDM2 activity by novel interaction with Ras-GAP binding proteins (G3BP)
Kim, M. M., Wiederschain, D., Kennedy, D. D., Hansen, E., & Yuan, Z.-M. (2007) · Oncogene · doi:10.1038/sj.onc.1210212 · Cited by 91 · see citing works
“MDM2’s inherent instability stems from its capacity to self-ubiquitylate (Kawai et al., 2003).”
BackgroundMicroRNA-34a Modulates MDM4 Expression via a Target Site in the Open Reading Frame
Mandke, P., Wyatt, N., Fraser, J., Bates, B., Berberich, S. J., & Markey, M. P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042034 · Cited by 90 · see citing works
“targeting MDM4 protein for degradation during the DNA damage response [9,10].”
BackgroundRegulation of p53-MDMX interaction by casein kinase 1 alpha
Chen, L., Li, C., Pan, Y., & Chen, J. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.15.6509-6520.2005 · Cited by 88 · see citing works
“Since DNA damage promotes degradation of MDMX (24, 31), it should also lead to reduced targeting of CK1 to MDM2 and thus reduce the level of MDM2 phosphorylation.”
BackgroundStommel, J. M., & Wahl, G. M. (2005) · Cell Cycle · doi:10.4161/cc.4.3.1522 · Cited by 87 · see citing works
MDMX (MDM4), a Promising Target for p53 Reactivation Therapy and BeyondPreprint
Marine, J., & Jochemsen, A. G. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026237 · Cited by 81 · see citing works
“In MDM2, the AD is essential for ubiquitination of p53, a function that cannot be fulfilled by the analogous domain of MDMX (Kawai et al. 2003b; Meulmeester et al. 2003).”
BackgroundInfluentialSpontaneous Tumorigenesis in Mice Overexpressing the p53-Negative Regulator Mdm4
Xiong, S., Pant, V., Suh, Y.-A., Van Pelt, C. S., Wang, Y., Valentin-Vega, Y. A., Post, S. M., & Lozano, G. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-1457 · Cited by 82 · see citing works
“After IR, Mdm4 protein levels decreased in spleens of Mdm4Tg15 mice consistent with previous in vitro data (23,28) (Figure 5A).”
Phosphorylation of MDMX Mediated by Akt Leads to Stabilization and Induces 14-3-3 Binding
Lopez-Pajares, V., Kim, M. M., & Yuan, Z.-M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m710030200 · Cited by 79 · see citing works
Milk-Derived Antimicrobial Peptides: Overview, Applications, and Future Perspectives
Singh, A., Duche, R. T., Wandhare, A. G., Kaur, J., Singh, B. P., Sihag, M. K., Singh, K. S., Sangwan, V., Talan, S., & Panwar, H. (2022) · Probiotics and Antimicrobial Proteins · doi:10.1007/s12602-022-10004-y · Cited by 86 · see citing works
“Kawai and coworkers used infusion of LF hydrolysate in mastitis-infected cows [142].”
MethodMancini, F., Conza, G. D., Pellegrino, M., Rinaldo, C., Prodosmo, A., Giglio, S., D’Agnano, I., Florenzano, F., Felicioni, L., Buttitta, F., et al. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.154 · Cited by 81 · see citing works
Wang, Y. V., Leblanc, M., Wade, M., Jochemsen, A. G., & Wahl, G. M. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.05.008 · Cited by 79 · see citing works
“, 2005), which appears to render Mdmx vulnerable to Mdm2-mediated ubiquitylation and proteasomal degradation (Kawai et al., 2003; de Graaf et al., 2003; Pan and Chen, 2003).”
Schedule-dependent interaction between anticancer treatments
Chen, S., Forrester, W. C., & Lahav, G. (2016) · Science · doi:10.1126/science.aac5610 · Cited by 73 · see citing works
Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity
Nomura, K., Klejnot, M., Kowalczyk, D., Hock, A. K., Sibbet, G. J., Vousden, K. H., & Huang, D. T. C. (2017) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3414 · Cited by 72 · see citing works
Targeting the MDM2-p53 protein–protein interaction for new cancer therapeutics
Wang, S., Zhao, Y., Bernard, D., Aguilar, A., & Kumar, S. (2012) · Topics in Medicinal Chemistry · doi:10.1007/978-3-642-28965-1_2 · Cited by 72 · see citing works
“Interestingly, in some cancer cell lines, MDM2 inhibitors can induce MDMX degradation, presumably mediated though p53-dependent up-regulation of MDM2 [50, 66, 76], which is known to ubiquitinate and degrade MDMX during DNA damage [77].”
BackgroundRegulation of the DNA damage response by ubiquitin conjugation
Brinkmann, K., Schell, M. J., Hoppe, T., & Kashkar, H. (2015) · Frontiers in Genetics · doi:10.3389/fgene.2015.00098 · Cited by 70 · see citing works
“…stabilization and activation (Cheng and Chen, 2010); however, MDM2 additionally promotes ubiquitylation and degradation of MDMX in response to DNA damage, again acting in a negative feedback loop (de Graaf et al., 2003; Kawai et al., 2003; Pan and Chen, 2003; Pereg et al., 2005; Xia et al., 2008).”
BackgroundMdmx promotes genomic instability independent of p53 and Mdm2
Carrillo, A. M., Bouska, A., Arrate, M. P., & Eischen, C. M. (2015) · Oncogene · doi:10.1038/onc.2014.27 · Cited by 69 · see citing works
FL118 Induces p53-Dependent Senescence in Colorectal Cancer Cells by Promoting Degradation of MdmX
Ling, X., Xu, C., Fan, C., Zhong, K. L., Li, F., & Wang, X. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0683 · Cited by 70 · see citing works
“HdmX degradation is mediated byMdm2-dependent ubiquitination after DNA damage (42, 43).”
BackgroundSingh, R. K., Iyappan, S., & Scheffner, M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610879200 · Cited by 69 · see citing works
The long and the short of it: the MDM4 tail so far
Haupt, S., Mejía-Hernández, J. O., Vijayakumaran, R., Keam, S. P., & Haupt, Y. (2019) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjz007 · Cited by 69 · see citing works
c-Abl Phosphorylates Hdmx and Regulates Its Interaction with p53
Zuckerman, V., Lenos, K., Popowicz, G. M., Silberman, I., Grossman, T., Marine, J.-C., Holak, T. A., Jochemsen, A. G., & Haupt, Y. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m809211200 · Cited by 68 · see citing works
Mdm2 promotes Cdc25C protein degradation and delays cell cycle progression through the G2/M phase
Giono, L. E., Resnick‐Silverman, L., Carvajal, L. A., Clair, S. S., & Manfredi, J. J. (2017) · Oncogene · doi:10.1038/onc.2017.254 · Cited by 67 · see citing works
Regulation of the Mdm2-p53 signaling axis in the DNA damage response and tumorigenesis
Carr, M. I., & Jones, S. N. (2016) · Translational Cancer Research · doi:10.21037/tcr.2016.11.75 · Cited by 70 · see citing works
“Notably, the turnover of MdmX is mediated by Mdm2 (126-128).”
BackgroundThe p53 response: Emerging levels of co-factor complexity
Coutts, A. S., & La Thangue, N. B. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.03.150 · Cited by 72 · see citing works
Phosphorylation and Degradation of MdmX Is Inhibited by Wip1 Phosphatase in the DNA Damage Response
Zhang, X., Lin, L., Guo, H., Yang, J., Jones, S. N., Jochemsen, A., & Lu, X. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-0634 · Cited by 67 · see citing works
“Previous study showed that Mdm2 is a critical E3 ubiquitin ligase that targets MdmX for degradation in cells (29).”
Tollini, L. A., Jin, A., Park, J., & Zhang, Y. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.06.006 · Cited by 66 · see citing works
“Mdm2 has previously been identified as the E3 ligase responsible for MdmX degradation (Kawai et al., 2003; Linke et al., 2008; Pan and Chen, 2003), and as expected, in the presence of Mdm2Y487A, stabilization of MdmX is observed (Figure 2F–”
Murine double minute 2: p53-independent roads lead to genome instability or death
Bouska, A. C., & Eischen, C. M. (2009) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2009.02.006 · Cited by 65 · see citing works
Xiong, X., Zhao, Y., Tang, F., Wei, D., Thomas, D. G., Wang, X., Liu, Y., Zheng, P., & Sun, Y. (2014) · eLife · doi:10.7554/elife.02236 · Cited by 66 · see citing works
“Furthermore, Mdm4 is a direct substrate of Mdm2 for targeted ubiquitylation and degradation (de Graaf et al., 2003; Kawai et al., 2003; Pan and Chen, 2003).”
InfluentialGiono, L. E., & Manfredi, J. J. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01967-06 · Cited by 62 · see citing works
“In fact, whereas after DNA damage Mdm2 promotes MdmX degradation (26, 35), downregulation of Mdm2 by siRNA caused an upregulation of MdmX protein levels (data not shown).”
BackgroundMaking sense of ubiquitin ligases that regulate p53
Jain, A. K., & Barton, M. C. (2010) · Cancer Biology & Therapy · doi:10.4161/cbt.10.7.13445 · Cited by 59 · see citing works
“33 During this process, Mdm2 may ubiquitinate itself and its partner, MdmX.24,34 Further investigations show that Mdm2-mediated regulation of p53 is more complex than initially thought, as Mdm2 also influences subcellular localization and transcriptional potential of p53 (Fig.”
BackgroundLi, Q., Li, J., Wen, T., Zeng, W., Peng, C., Yan, S., Tan, J., Yang, K., Liu, S., Guo, A., et al. (2014) · Oncotarget · doi:10.18632/oncotarget.2201 · Cited by 57 · see citing works
“As a critical inhibitor of G1 cell cycle kinase, the expression of p21 can be regulated by either p53-dependent or independent manner [31-33].”
BackgroundTargeting the Ubiquitin-Mediated Proteasome Degradation of p53 for Cancer Therapy
DeVine, T., & Dai, M. (2013) · Current Pharmaceutical Design · doi:10.2174/1381612811319180009 · Cited by 57 · see citing works
p53 ubiquitination by Mdm2: A never ending tail?
Coutts, A. S., Adams, C., & Thangue, N. B. L. (2009) · DNA repair · doi:10.1016/j.dnarep.2009.01.008 · Cited by 56 · see citing works
Levav-Cohen, Y., Goldberg, Z., Zuckerman, V., Grossman, T., Haupt, S., & Haupt, Y. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.03.152 · Cited by 55 · see citing works
Phillips, A., Teunisse, A., Lam, S., Lodder, K., Darley, M., Emaduddin, M., Wolf, A., Richter, J., de Lange, J., Verlaan-de Vries, M., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.129726 · Cited by 55 · see citing works
Secondary interaction between MDMX and p53 core domain inhibits p53 DNA binding.
Wei, X., Wu, S., Song, T., Chen, L., Gao, M., Borcherds, W., Daughdrill, G. W., & Chen, J. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1603838113 · Cited by 50 · see citing works
“MDMX level is controlled by MDM2-mediated ubiquitination in a stressdependent fashion (11, 12).”
BackgroundTargeting the ubiquitin–proteasome system to activate wild-type p53 for cancer therapy
Allende-Vega, N., & Saville, M. K. (2009) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2009.10.004 · Cited by 51 · see citing works
A Critical Role for Noncoding 5S rRNA in Regulating Mdmx Stability
Li, M., & Gu, W. J. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.08.020 · Cited by 50 · see citing works
“Notably, like p53, Mdmx is ubiquitinated and degraded by Mdm2 (de Graaf et al., 2003; Kawai et al., 2003; Pan and Chen, 2003); several studies indicate that degradation of Mdmx is crucial for optimal activation of p53 function (Jin et al., 2006; LeBron et al., 2006; Lopez-Pajares et al., 2008;…”
Autoinhibition of MDMX by intramolecular p53 mimicry
Chen, L., Borcherds, W. M., Wu, S., Becker, A., Schönbrunn, E., Daughdrill, G. W., & Chen, J. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1420833112 · Cited by 49 · see citing works
“MDMX levels are controlled by MDM2-mediated ubiquitination in a stress-dependent fashion (6, 7).”
BackgroundMDM2 expression is repressed by the RNA-binding protein RNPC1 via mRNA stability
Xu, E., Zhang, J., & Chen, X. (2012) · Oncogene · doi:10.1038/onc.2012.238 · Cited by 48 · see citing works
“Interestingly, we also found that in H1299 and SW480 cells, the level of MDMX, the MDM2 homolog, was increased upon expression of RNPC1, which is likely due to decreased expression of MDM2, an E3 ligase of MDMX [32, 33].”
BackgroundCasein Kinase 1α Regulates an MDMX Intramolecular Interaction To Stimulate p53 Binding
Wu, S., Chen, L., Becker, A., Schönbrunn, E., & Chen, J. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00851-12 · Cited by 48 · see citing works
“nation in a stress-dependent fashion (19, 37).”
Zhang, S., Lou, J., Li, Y., Zhou, F., Yan, Z., Lyu, X., & Zhao, Y. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00940 · Cited by 47 · see citing works
Marcar, L., Ihrig, B., Hourihan, J. M., Bray, S. E., Quinlan, P., Jordan, L. B., Thompson, A. M., Hupp, T. R., & Meek, D. W. (2015) · PLoS ONE · doi:10.1371/journal.pone.0127713 · Cited by 42 · see citing works
“Firstly, it is a stimulatory partner of MDM2 [26] that is itself regulated by MDM2-mediated ubiquitylation [27,28,29].”
BackgroundSpinnler, C., Hedström, E., Li, H., de Lange, J., Nikulenkov, F., Teunisse, A. F. A. S., Vries, M. V., Grinkevich, V. V., Jochemsen, A. G., & Selivanova, G. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.45 · Cited by 42 · see citing works
Competitive ubiquitination activates the tumor suppressor p53
Li, X., Guo, M., Cai, L., Du, T., Liu, Y., Ding, H., Wang, H., Zhang, J., Chen, X., & Yan, C. (2019) · Cell Death and Differentiation · doi:10.1038/s41418-019-0463-x · Cited by 41 · see citing works
Structural basis for DNA damage-induced phosphoregulation of MDM2 RING domain
Magnussen, H., Ahmed, S. F., Sibbet, G. J., Hristova, V. A., Nomura, K., Hock, A. K., Archibald, L. J., Jamieson, A. G., Fushman, D., Vousden, K. H., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15783-y · Cited by 37 · see citing works
MDM4 (MDMX) Overexpression Enhances Stabilization of Stress-induced p53 and Promotes Apoptosis
Mancini, F., Gentiletti, F., D'Angelo, M., Giglio, S., Nanni, S., D’Angelo, C., Farsetti, A., Citro, G., Sacchi, A., Pontecorvi, A., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m311793200 · Cited by 38 · see citing works
Cisplatin causes cell death via TAB1 regulation of p53/MDM2/MDMX circuitryPreprint
Zhu, Y. Y., Regunath, K., Jacq, X., & Prives, C. L. (2013) · Genes & Development · doi:10.1101/gad.212258.112 · Cited by 39 · see citing works
“Second, it is well established that some DNA damage-inducing agents (via ATM activation) elicit MDM2 degradation of MDMX (Kawai et al. 2003; Chen et al. 2005; Okamoto et al. 2005; Pereg et al. 2005; Jin et al. 2006).”
BackgroundMDM2 and MDMX in Cancer and Development
Marine, J. (2011) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/b978-0-12-380916-2.00003-6 · Cited by 38 · see citing works
Functions of MDMX in the Modulation of the p53‐Response
Lenos, K., & Jochemsen, A. G. (2011) · BioMed Research International · doi:10.1155/2011/876173 · Cited by 38 · see citing works
“And indeed, in most cases, a decrease in MDMX levels is observed and some experiments have shown that prevention of that MDMX degradation is inhibiting the p53 response [31, 35].”
BackgroundDNA damage-induced signalling in ataxia-telangiectasia and related syndromes
Lavin, M. F., & Kozlov, S. (2007) · Radiotherapy and Oncology · doi:10.1016/j.radonc.2007.04.032 · Cited by 38 · see citing works
Mouse bites dogma: how mouse models are changing our views of how P53 is regulated in vivo
Wahl, G. M. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401911 · Cited by 37 · see citing works
The ATM regulated DNA damage response pathway as a chemo- and radiosensitisation target
Alao, J. P. (2009) · Expert Opinion on Drug Discovery · doi:10.1517/17460440902835475 · Cited by 36 · see citing works
“It has been proposed that ATM destabilises both Mdm2 and Mdmx by preventing their interaction with the HAUSP (herpes virus-associated ubiquitin-specific protease) deubiquitylating enzyme [70].”
BackgroundInfluentialA Novel ATM/TP53/p21-Mediated Checkpoint Only Activated by Chronic γ-Irradiation
Cao, L., Kawai, H., Sasatani, M., Iizuka, D., Masuda, Y., Inaba, T., Suzuki, K., Ootsuyama, A., Umata, T., Kamiya, K., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0104279 · Cited by 37 · see citing works
“Western blot analysis Western blot analysis was performed using 10 mg of whole cell extracts as described [9], with modifications.”
MethodResultInfluentialDe Clercq, S., Gembarska, A., Denecker, G., Maetens, M., Naessens, M., Haigh, K., Haigh, J. J., & Marine, J.-C. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00330-10 · Cited by 35 · see citing works
“Mdm4 levels rapidly decline in an Mdm2dependent manner following DNA damage (6, 23, 38).”
BackgroundThe roles of MDM2 and MDMX phosphorylation in stress signaling to p53
Chen, J. (2012) · Genes & Cancer · doi:10.1177/1947601912454733 · Cited by 33 · see citing works
“The MDMX level is controlled by MDM2-mediated ubiquitination in a stress-dependent fashion.(42,100,101) A fraction of MDMX from cells with DNA damage has delayed migration consistent with phosphorylation in an ATM-dependent fashion.”
BackgroundAbnormal MDMX degradation in tumor cells due to ARF deficiency
Li, X., Gilkes, D., Li, B., Cheng, Q., Pernazza, D., Lawrence, H., Lawrence, N., & Chen, J. (2012) · Oncogene · doi:10.1038/onc.2011.534 · Cited by 32 · see citing works
“The acidic region of MDM2 is important for ubiquitination and degradation of p53 through unknown mechanisms (Kawai et al 2003b, Meulmeester et al 2003).”
Stochastic Modeling and Simulation of the p53-MDM2/MDMX Loop
Cai, X., & Yuan, Z.-M. (2009) · Journal of Computational Biology · doi:10.1089/cmb.2008.0231 · Cited by 32 · see citing works
“The half-life of MDMX is about 3 hours, which is almost the same as the experimental measurements (Kawai et al., 2003).”
InfluentialNaderi, E. H., Jochemsen, A. G., Blomhoff, H. K., & Naderi, S. (2011) · Neoplasia · doi:10.1593/neo.11542 · Cited by 31 · see citing works
“Indeed, down-regulation of HDMX protein levels in response to DNA damage is critical for p53 accumulation [46,49].”
BackgroundMacchiarulo, A., Giacchè, N., Carotti, A., Baroni, M., Cruciani, G., & Pellicciari, R. (2008) · Journal of Chemical Information and Modeling · doi:10.1021/ci800146m · Cited by 29 · see citing works
Zu, G., Yao, J., Ji, A., Ning, S., Luo, F., Li, Z., Feng, D., Rui, Y., Li, Y., Wang, G., et al. (2016) · Journal of Molecular Medicine · doi:10.1007/s00109-016-1464-6 · Cited by 29 · see citing works
- Authors
- Kawai, H., Wiederschain, D., Kitao, H., Stuart, J., Tsai, K. K. C., & Yuan, Z.-M.
- Affiliations
- Harvard University (US)
- Corresponding author
- Yuan, Zhi-Min
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-11
- Volume
- 278
- Issue
- 46
- Pages
- 45946-45953
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2070023783
- Cited by
- 163
- References
- 15
- Citations by year
- 2025: 2 · 2023: 4 · 2022: 4 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 6 · 2016: 15 · 2015: 4 · 2014: 11 · 2013: 6 · 2012: 14
- FWCI
- 3.90
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5t32es007155-24)
- National Cancer Institute (R01CA085679, R01CA85679)
- National Institute of Environmental Health Sciences (T32-ES07155)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- MDMX, MDM2, p53 activation, DNA damage response, proteasomal degradation, protein degradation, genotoxic stress, p53 regulation
- MeSH terms
- Cell Cycle, Cysteine Endopeptidases, DNA Damage, Humans, Microscopy, Fluorescence, Multienzyme Complexes, Nuclear Proteins, Plasmids, Precipitin Tests, Proto-Oncogene Proteins, Retroviridae, Time Factors, Transfection, Blotting, Western, Down-Regulation, Tumor Suppressor Protein p53, Reverse Transcriptase Polymerase Chain Reaction, Ubiquitin, Cell Line, Tumor, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-mdm2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
